Key Trials at ASCO 2023 Highlight Role of Perioperative Treatment Approaches in NSCLC

Findings from pivotal trials in non–small cell lung cancer (NSCLC) presented at the 2023 ASCO Annual Meeting displayed the potential benefit for perioperative treatment with EGFR TKIs or immune checkpoint inhibitors in select patient populations, according to Jarushka Naidoo, MBBCh.

Data presented at the meeting included the overall survival (OS) analysis from the phase 3 ADAURA trial (NCT02511106), which showed that adjuvant osimertinib (Tagrisso) produced a statistically significant and clinically meaningful improvement in OS vs placebo in patients with resected stage IB to IIIA EGFR-mutant NSCLC (HR, 0.49; 95.03% CI, 0.33-0.73; P = .0004).¹

Additionally, data from the phase 3 KEYNOTE-671 trial (NCT03425643) showed that pembrolizumab (Keytruda) plus chemotherapy followed by resection and adjuvant pembrolizumab monotherapy improved event-free survival (EFS) and pathologic responses compared with neoadjuvant placebo plus chemotherapy, followed by adjuvant placebo, in patients with stage II or IIIA/B resectable NSCLC. The 24-month EFS rate in the experimental arm was 62.4% vs 40.6% in the placebo arm (HR, 0.58; 95% CI, 0.46-0.72; P < .00001).²

“The neoadjuvant/adjuvant perioperative space in NSCLC cancer is a very dynamic field and is exploding with data. KEYNOTE-671 is an impressive study with results that are very meaningful to our field,” Naidoo said in an interview with OncLive® News Network: On Location during the meeting. “[Meanwhile, OS data from ADAURA] will affirm what many are currently doing, which is treating [patients] with adjuvant osimertinib.”

In the interview, Naidoo discussed the clinical significance of datasets from several phase 3 trials presented at the 2023 ASCO Annual Meeting, including ADAURA, KEYNOTE-617, CheckMate 816 (NCT02998528), and CheckMate 9LA (NCT03215706). She also expanded on potential roles for novel treatment approaches in NSCLC, according to data from the phase 1/2 ARTEMIDE-01 (NCT04995523), phase 3 KEYNOTE-789 (NCT03515837), and phase 3 LUNAR (NCT02973789) trials.

Naidoo is a professor of medical oncology at Royal College of Surgeons Ireland Cancer Centre, and a consultant medical oncologist at Beaumont Hospital Dublin.

OncLive: What presentations from the 2023 ASCO Meeting were you most looking forward to seeing this year?

Naidoo: There were several highlights in the field of lung cancer. One of the clear highlights [came from] a plenary presentation on OS data from the phase 3 ADAURA study, examining osimertinib in early-stage, resected, EGFR-mutant NSCLC. These are very important and practice-changing findings. The second presentation that is an equal highlight was the KEYNOTE 671 study, which [evaluated] the use of perioperative immunotherapy with pembrolizumab in patients with resected, early-stage NSCLC.

When the disease-free survival (DFS) data from ADAURA were initially reported, the field appeared to be split on whether adjuvant osimertinib was going to become a standard of care. How have the OS findings presented at this meeting helped settle this debate?

[This trial] speaks to the debate about what is an appropriate end point to measure benefit in patients with early-stage NSCLC, and that's where we saw the split [in opinion]. Those who [supported] ADAURA [following the publication of DFS data] were very impressed by the magnitude of the DFS benefit and felt that this was likely to result in OS benefit, or that that degree of DFS benefit itself was clinically meaningful. What we've seen [with the OS data] is a confirmation of that thought process and, most importantly, a benefit for these patients.

How will OS data from the ADAURA trial affirm practice patterns regarding the use of adjuvant osimertinib?

We all accept that OS is the gold-standard end point. Demonstrating a significant OS benefit truly solidifies osimertinib as a treatment [in resected, early-stage NSCLC]. In some jurisdictions around the world, this has yet to be approved ,or approval is pending, [based on] this confirmation. These [OS data] will provide that confirmation and make us all feel confident to proceed with that approach.

What were some of the key questions in the perioperative NSCLC space that were addressed in KEYNOTE-671?

This large, phase 3, randomized study screened [1364] patients, and [a total of 797] patients [were randomly assigned] to the investigational arm of up-front cisplatin-based chemotherapy [combined] with pembrolizumab [or] chemotherapy alone. [Patients then received] one year of adjuvant pembrolizumab compared with placebo. This study demonstrated an impressive, significant EFS benefit with a hazard ratio of 0.58. The data for OS are immature, but it appears that there is some separation [of] the curves that is occurring in terms of OS, which is very exciting for the field.

Two or three elements of the study have filled in or are [beginning to] fill in gaps in our knowledge on perioperative therapy. [Lead study author] Heather Wakelee, MD, of Stanford Health, separated out what proportion of patients completed 3 cycles of neoadjuvant chemo-immunotherapy vs those who completed 4 cycles. This ties in with CheckMate 816, in which patients received 3 [cycles], and [the phase 3] Neotorch study [NCT04158440], which was presented as a virtual plenary at the 2023 ASCO Annual Meeting, where 3 cycles were given [before] surgery followed by 1 cycle after surgery. [These data from KEYNOTE-671 are] trying to disentangle this question. Dr Wakelee showed that [74.5%] of patients [in the pembrolizumab arm] received all 4 cycles, and [87.4%] received 3 cycles. That's interesting, and really should raise questions about when we should give 3 vs 4 [cycles].

The second question this study [attempting to answer] was: what is the benefit for 1 year of adjuvant pembrolizumab on top of the CheckMate 816 regimen, which did not feature an adjuvant approach? It appears that adjuvant pembrolizumab does have a role in select patients. We'll have to [debate] which patients [derive a benefit], whether those are the patients who have a pathologic response or don't have a pathologic response, but these data can now be examined as they mature.

Lastly, Dr Wakelee commented on surgical outcomes, which are very important in this field. [The data] showed that [11.4%] of patients [in the experimental arm] had a pneumonectomy, which is in keeping with what we know.

How might the presentation of 4-year survival data, as well as patient outcomes by histologic subtype, from CheckMate 9LA help clarify treatment selection strategies in clinical practice?³

These long-term survival data are important because they give us a sense of the tail on the curve. When we're explaining to patients what their likely outcomes are, we [can provide them with] more data as these data are presented. I don't think it necessarily changes what we do now. We know that CheckMate 9LA [regimen consists of] 2 doses of chemotherapy followed by ipilimumab [Yervoy] and nivolumab [Opdivo], and this is associated with one of the best sets of survival outcomes. There are some toxicity concerns with giving a full drug combination. Treatment selection is probably going to be the same [with] these data, but the findings inform our discussion with patients [about] their likely outcomes.

Neoadjuvant nivolumab and platinum-doublet chemotherapy is currently FDA approved and has a recommendation for approval by the European Medicines Agency based on data from CheckMate 816. Will the presentation of 3-year results by definitive surgery from this study affect the regimen's use from a multidisciplinary standpoint?⁴

Surgical data are very important for the perception of this treatment in the field. In early-stage NSCLC, it’s not just medical oncologists treating [patients]; it’s also surgeons and radiation oncologists. Presenting data for different surgical approaches and showing what those outcomes are gives our colleagues in surgery a similar comfort about choosing one approach vs another, what those surgical complications are, when they occur, the different types of surgery [available], and how this new treatment impacts [surgery]. [These data] will help foster this approach in a multidisciplinary manner.

Results from the ARTEMIDE-01 trial have garnered substantial interest within the field of thoracic oncology. What is the appeal of utilizing a bispecific antibody in patients with advanced or metastatic NSCLC who were resistant to prior immunotherapy?⁵

[Treatment] following an immune checkpoint inhibitor is currently somewhat of a barren wasteland. Right now, we give single-agent chemotherapies such as docetaxel, and the response rates are relatively modest. An approach that allows us to raise the bar and to build on existing types of treatment like immunotherapy, which have resulted in tails on the [survival] curve, is very appealing to us. A bispecific has the potential to provide the benefit of anti–CTLA-4 [therapy], potentially mitigating a little bit of toxicity and avoiding some of the chemotherapies that haven't been very successful. [However], this is a difficult space to raise the bar, so [we'll] see what the data show.

How do chemoimmunotherapy approaches like the KEYNOTE-789 regimen of pembrolizumab plus chemotherapy measure up against other approaches being evaluated in this space?⁶

KEYNOTE-789 is examining whether patients with EGFR-mutant lung cancer may benefit from the addition of immunotherapy to platinum-doublet chemotherapy. This is sort of a separate and parallel question about whether immunotherapy plays a role in oncogene-addicted cancers. So far, we haven't seen that immunotherapy has been effective. In many instances, this group of patients has wondered when or how they should access immunotherapy.

What is the appeal and potential role of tumor treating fields (TTFields) in metastatic NSCLC following progression on platinum-based chemotherapy, according to results from the LUNAR trial?⁷

This is a completely new approach. We know that [use of] TTFields are associated with some degree of benefit in patients with glioblastoma multiforme, and this [study] is attempting to expand the use of this treatment to other tumor types such as NSCLC. It's a very innovative technology that is delivered in a localized fashion. It would be a very different approach to standard investigational drugs we give as medical oncologists. However, the data will be the data, and we should be open minded about whether this [approach] confers a survival benefit.

If we do see an impressive response, we will have to rethink how we treat lung cancer. It will mean that we need to approach things slightly differently. Our support staff will need to be skilled at placing and managing these devices. It will be a new way of approaching [treatment], but let the data speak to us and we'll take it from there.

References

1. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 17):LBA3. doi:10.1200/JCO.2023.41.17_suppl.LBA3
2. Wakelee HA, Liberman M, Kato T, et al. KEYNOTE-671: randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. J Clin Oncol. 2023;41 (suppl 17):LBA100. doi:10.1200/JCO.2023.41.17_suppl.LBA100
3. First-line (1L) nivolumab (N) + ipilimumab (I) + chemotherapy (C) vs C alone in patients (pts) with metastatic NSCLC (mNSCLC) from CheckMate 9LA: 4‑y clinical update and outcomes by tumor histologic subtype (THS). J Clin Oncol. 2023;41(suppl 17):LBA9023. doi:10.1200/JCO.2023.41.17_suppl.LBA9023
4. Spicer J, Forde PM, Provencio M, et al. Clinical outcomes with neoadjuvant nivolumab (N) + chemotherapy (C) vs C by definitive surgery in patients (pts) with resectable NSCLC: 3-y results from the phase 3 CheckMate 816 trial. J Clin Oncol. 2023;41 (suppl 16):8521. doi:10.1200/JCO.2023.41.16_suppl.8521
5. Rohrberg KS, Brandão M, Alvarez EC, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD2936, a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-experienced advanced/metastatic non-small-cell lung cancer (NSCLC): First report of ARTEMIDE-01. J Clin Oncol. 2023;41 (suppl 16):9050. doi:10.1200/JCO.2023.41.16_suppl.9050
6. Yang, JC-H, Lee DH, Lee JS, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: phase 3 KEYNOTE-789 study. J Clin Oncol. 2023;41(suppl 17):LBA9000. doi:10.1200/JCO.2023.41.17_suppl.LBA9000
7. Leal T, Kotecha R, Ramlau R, et al. Tumor Treating Field (TTFields) therapy with standard of care (SOC) in metastatic non-small cell lung cancer (mNSCLC) following platinum failure: Randomized, phase 3 LUNAR study. J Clin Oncol. 2023;41(17):LBA9005. doi:10.1200/JCO.2023.41.17_suppl.LBA9005